Stroke extends earlier than the Greco-Roman civilization which is usually thought to be the founder of modern medicine. In his historical review on stroke, Karenberg presented an illustrated figure of sources of stroke in antiquities dating to 500 BC [4]. Yet, this is not the case as the description of stroke or apoplexy dates to the ancient Egyptian civilization whether in discovered papyri in tombs or temple inscriptions as the one dating 2455 BC on the tomb of the Vizier Westptah [5].

Medicine and surgery extend to the early civilizations and the basis of modern medicine is based in many aspects on the Greco-Roman philosophers and Muslim physicians who based some of their theories on earlier knowledge from the Egyptian, Chinese, Sumerians, Babylonians, Assyrians, and Persian civilizations [6].

Egyptian civilization

An Egyptian mummy (2680 years) representing a possible case of left hemiparesis was discovered in Luxor. After working on the body radiologically and forensically, it was concluded that it belonged to a female in her late twenties to early forties. The mummy was taking a typical position of left hemiparesis with an extensive contracted and adducted shoulder, face facing down, flexion of the left arm and forearm placed on the chest with over flexed wrist up to twisting of the left hand, the left leg was overextended as donated by placing its fibula more anteriorly than the right leg and the foot was planter flexed. The body of the mummy was fixed with sticks to keep it in an erect position. A walking stick was found beside the mummy [7].

Etiologically modern medicine can place a differential diagnosis ranging from infectious diseases to cerebrovascular insults which is more favorable as other diseases usually in earlier times were fatal within a short time frame and not affording time to live with a disability up to contracture deformities [7, 8].

Despite no direct link in this discovered young female stroke patient to cardiovascular insults yet being young female and as current clinical practice return stroke in young to either vessel-to-vessel embolization, cardiac source, or vasculitis secondary to autoimmune, hypercoagulable states or thrombophilia disorders; an etiological cardiovascular cause can be considered in this 747–656 BC discovered mummy [7, 8].

Egyptian papyri mentioned hemiparesis and quadriparesis yet returning them to spine conditions [9]. It is worth mentioning that the heart and the vascular system were described in some detail yet in a primitive way in the ancient Egyptian civilization. Egyptians considered the heart the source of all body fluids and is connected to different body parts through 22 identified vessels, they knew that the heart and the lung are connected and that air through both is transmitted to the rest of the body [10, 11].

In Ancient Egypt pulsation was thought to originate from blood vessels, and arterial aneurysms were described and were managed through cautery through which excessive pulsation is stopped [11].

In the nineteenth century, atherosclerosis was discovered in royal pharaonic mummies. Further analysis was performed using the Horus Study. It was found that atherosclerosis was present in 85% of examined mummies the oldest dating 1981 BC and results were 38% common among different civilizations making atherosclerosis a common disorder in antiquities at least in the high social class [10, 12].

In the Horus study, carotid atherosclerosis was present in 8 of 52 studied mummies, while it was a common finding in the coronaries and the carotids in 2. In 6 mummies atherosclerosis was found within the aorta [12].

The mummy of Menephtah (1213–1203 BC) was found to be afflicted with atheromatous lesions within the aorta. Despite being old enough when he ruled Egypt which might reason for atherosclerosis other mummies who showed atherosclerosis in the Horus study were of different ages [12, 13].

Nowadays, it is proven that inflammation and inflammatory disorders including autoimmune conditions accelerate vasculitis and atherosclerosis. Inflammatory disorders might date to ancient civilizations. Another explanation that is not related to hypertension or diabetes which are not ruled out nor accused, since their prevalence is not known in ancient Egypt is smoke from the cooking fire that generates proatherogenic methane and gelatinase [14].

Myocardial infarction and angina were well known in the Egyptian civilization and were linked to eminent death as written in the Ebers papyrus, yet whether angina was dreadful up to death or acted as a comorbid condition to stroke is still mysterious in ancient medicine [15].

Sumerian, Babylonian, and Assyrian civilizations

Unlike the Egyptians, the Mesopotamian civilization which is nowadays modern Iraq did not describe the inner organs of the body and there are no mummies to return to for autopsy. Yet, like the Egyptians, the Mesopotamians outweighed the heart and considered it the center of the body and its main organ [16]. As the Egyptians, they were acquainted with pulsation and identified the heart as its origin and that pulse cessation was equivalent to death [17].

What makes the Mesopotamian civilization a major source for the localization of stroke is the precise description of symptoms on clay tablets. In tablet 27, there is a detailed description of unilateral facial weakness and paralysis on one side of the body. Lateralizing signs were well known as there was a link between the development of aphasia, right-sided weakness, and left hemisphere lesions, while left-sided weakness without aphasia was linked to the right hemisphere. Meanwhile, the Assyrians had a prognostic idea that the left hemisphere injuries that were accompanied by aphasia usually had a less favorable outcome and that if there was a motion preserved along the distal extremities without dysphasia then a favorable outcome was proposed [16, 18]. This resembles what modern medicine accounts for in the National Institutes of Health stroke scale scores (NIHSS) [19].

Genetic load as a direct causative cause of stroke was not considered except in modern science [20, 21], yet the Mesopotamians were the first to introduce genetics in stroke more than 2500 years, documented in a timeline between 692 and 681 BC that two ruling brothers (Humban-Nimena III and Humban-Haltash I) died out of apoplexy stating that one presentation was speech affection “mouth seized to talk” [22].

Chinese civilization

Stroke in its ancient term apoplexy has been mentioned in the context of comorbid neurological disorders as post-stroke epilepsy since 475 BC. In a Chinese book for diseases and prescriptions, 52 diseases were identified including different forms of stroke that range from mild to severe with disturbed consciousness. As the Mesopotamians, the Chinese linked a stroke with speech affection, those with mild speech affection were considered treatable, while those with loss of verbal abilities were considered untreatable reflecting that although ancient medicine was not able to identify major vessels and its link to a massive stroke, yet they were able to identify massive stroke through its signs which donate cortical affection [23].

A Chinese medical book by Zhang Zhongjing in the second century AD was considered the first source classifying stroke/apoplexy into mild and massive forms, where the classification was mild if the consciousness was maintained and with sensory or motor affection in the extremities along one side of the body with or without difficulty in speech or deviation of mouth. Meanwhile, a massive form was in case of disturbed conscious level with paralysis and unclear speech. Owing to his classification, Zhongjing was considered Hippocrates of China [23].

The Greco-Roman apoplexy theories

The Greco-Roman theories of stroke/apoplexy extended between 500 BC and 800 AD and began with Hippocrates and ended with Galen.

Although modern medicine considers Greco-Roman medicine the basis for modern science yet once digging in-depth into the theories behind diseases that the Greco-Roman philosophers were up to one will deny many. One theory that prevailed along 1200 years was that functions of the brain were located within the ventricular system rather than the brain parenchyma. Diseases were thought to originate because of an imbalance between four fluids present in the body and the brain chambers (humoral theory of Hippocrates) [6].

Yet, the Greco-Roman theories were accurate in some basic links linking stroke/apoplexy symptoms and severity as they identified stroke affecting breathing and severity as well as fatality which is nowadays explained based on brainstem compression and herniation [6].

The Muslim golden age

From 800 to 1200 AD, Muslims led the world in different fields of science and medicine. A new relationship emerged between the heart and the brain, both were considered vital organs, and stroke/apoplexy might originate from the heart and affect the brain which is cardioembolic stroke.

Haly Abbas and Ibnisina (Avicenna in Latin) stated that the ventricular system might be congested and filled with a mixture of fluids stated earlier by Hippocrates and Galen, stating that it might be filled with blood. This was the basics of what is known as hemorrhagic stroke and interventricular hemorrhage. Brain edema was introduced by Ibnisina stating that in severe stroke the brain is congested and the ventricles are occluded [6].

Muslim physicians also elaborated on how the heart was connected to the brain through blood vessels and that one of the fluids stated earlier in the humoral theory or even thick blood might occlude these vessels causing a stroke. This might be the earliest facts behind thrombosis, and embolization [6].

Rhazes introduced the fact that stroke was a result of damage to the brain parenchyma, not the ventricles and that the ventricular system involvement is just a part of the pathology taking place within the brain parenchyma [6].

One of the thoughts of Galen was the permeability of the intracardiac septum and that this was the way through which blood was transferred from the lungs to the left ventricle and then to the rest of the body. This theory was denied by Ibn al-Nafis in describing the pulmonary circulation. Ibn al-Nafis also explained that the arterial and the venous sides of the pulmonary circulation are interconnected within the lung by narrow vessels which were later termed the pulmonary capillaries [24].

Galen's theory is only rational in modern medicine in pathological conditions that might cause paradoxical emboli to the brain as in the case of patent foramen ovale [25, 26].

Al-Akhawayni Bukhari (Joveini in Latin) described how the brain is supplied by two main vessels that pass on either side of the neck (the carotids in modern medicine), on entering the skull, they are divided into a network to supply the entire brain. This was seven centuries before the identification of the circle of Willis [27].

By the fifteenth century, the time of the fall of Al-Andalus the golden age of Islam began to subside, and the European Renaissance took over:

In 1599, the term stroke was first used in the English literature to reflect striking suddenly, initially, it reflected hitting something or an unexpected sudden important event, and since cerebrovascular accidents are sudden, unexpected and what follows differs from what proceeds in activities of daily living so stroke as a regular English noun began to reflect what Cambridge dictionary defines as a sudden change in the blood supply to a part of the brain, with its consequences on the loss of functions of the affected part as the ability to move [28, 29].

For both Greek and Chinese Hippocrates, the term apoplexy was the preferred term that reflects hemiparesis secondary to a brain insult and until years ago the term apoplexy was still preferred by some physicians to reflect the dramatic and sudden nature of the insult resembling thunder-lightning [30].

What Hippocrates and Galen as well as what Muslim physicians and philosophers considered a cause of stroke/apoplexy which was the thickening of fluids or blood viscosity with an increase of wastes within such fluids was later modified in the eighteenth century with the identification and approval of the blood pressure concept [6, 30]. Before the identification of blood pressure and its management, stroke/apoplexy was managed by blood letting out to return the balance between the fluids of the body and remove waste products and this is the cupping in the Muslim traditions, which was later modified to the venesection introduced by Osler in 1892 as a way of reducing blood pressure after stroke [6, 30, 31].

Osler’s theory was not abandoned except in 1935 when venesection was no longer considered in dealing with stroke/apoplexy. Reducing blood pressure is one of the main aspects of secondary prevention of stroke in modern medicine yet it is not a matter of removing waste products or restoring the balance between body fluids as thought earlier [6, 32, 33].

The pathogenesis of stroke was not discovered in full until recently and even today some causes of stroke are still unknown and termed embolic stroke of undetermined source [34, 35]. Many lay people still believe in superpowers and supernatural events as a cause behind their illnesses which is much more common in disorders that are bizarre in presentation as epilepsy yet for centuries up to the nineteenth century black magic and superpowers were considered a cause of stroke [6, 30, 36].

In the European Renaissance era, there were no scales that could be relayed upon to reflect the severity and outcome of stroke as the current ones like the modified Rankin scale and the NIHSS [19, 37], yet as ancient civilizations used to link symptoms to severity and mortality such as speech arrest or breathing affection, in Napoleon’s era suffering stroke for a second time was of worse outcome and a third was usually considered fatal as what Corvisart warned Napoleon about [30, 38].

In the eighteenth century and as bedside medicine began to emerge, risk factors began to have a role in explaining the etiological causes of stroke. Modern medicine continues nowadays to approve special habits and risks such as a short neck and apnea, a sedentary life with an absence of physical activity, a diet rich in carbohydrates, alcohol intake, and smoking. In addition, in the eighteenth century, it was stated that “living a moderate life is protective and an excess of anything is dangerous and might provoke apoplexy” [39, 40].

As for recovery, the modern neuroplasticity concept was not in full action in the eighteenth century, and in the nineteenth century, the prognosis of stroke/apoplexy was guarded if no recovery began to appear within 3 months and if contractures happened to emerge [30, 41].

By the end of the eighteenth century, physicians began to approach diseases through pathology and disruption of anatomy through autopsy [42]. With the discovery of cerebral circulation by Willis and the identification of areas responsible for expression and later comprehension by Broca and Wernicke the term cerebrovascular disease emerged, and apoplexy was discarded [43]. Another explanation for the emergence of cerebrovascular disease term instead of apoplexy which used to reflect the dramatic nature of the illness is that autopsies began to show that the commonest cause of apoplexies was ischemia rather than hemorrhage and although it is of sudden nature it is not drastically as in the case of hemorrhage [4].

Discovering the arterial polygon of the brain

known as the circle of Willis, the anastomotic arterial tree at the base of the skull that supplies the brain with blood and provides anatomical protection against the development of stroke through the redirection of blood flow through its unique anastomosis.

Surprisingly such arterial anastomosis is not truly a circle nor directly credited to Sir Thomas Willis.

Since antiquity and during the Greco-Roman civilization dissections were not routinely done on humans yet occasionally were performed on animals and what is found within animals was reflected on humans [44].

Galen who is best known by Western civilization as one of the founders of anatomy discovered a mesh of complex blood vessels on the base of the skull of a bull and termed it the rete mirabile “wonderful net”, claiming to be present in the human brain.

The rete mirabile was an undeniable fact until the European Renaissance when the dissection of human bodies was approved and at this period which was nearly thirteen centuries later the rete mirabile was denied [44, 45].

The first anatomist to deny Galen’s wonderful net was Andreas Vesalius in the sixteenth century and owing to true human body dissection he reached a frank conclusion that there was no rete mirabile along the base of the human skull. Moreover, Vesalius dissected the area surrounding the pituitary gland, despite his inability to identify its content yet, he localized the two sleeping arteries (the internal carotid arteries”ICA”) and within some of his illustrations, a bifurcated right ICA was drawn which might be one of the first known variants in the later on termed circle of Willis, also segment A1 and A2 of the anterior cerebral artery (ACA) were represented, the middle cerebral artery (MCA), and the posterior communicating artery (PCOM) [44, 46, 47].

Another variant that was unintentionally described by Vesalius was the absence of an anterior communicating artery (ACOM). So, credit must be given to Vesalius for providing a scientific path for further discoveries of the arterial supply of the brain with two variants [44].

Gabriel Fallopius followed Vesalius and described a portion of the posterior arterial tree, he described the union of the two vertebral arteries (VA) and then their division as well as the union of the ICAs, described some of the branches originating from what later on identified as basilar artery (BA) as well as describing the PCOM, yet what Fallopius failed in was his inability to identify the anastomosis of vessels. The contribution of Fallopius was the initial identification even by chance of the BA perforators [44].

Within the second half of the sixteenth and the first quarter of the seventeenth centuries, the full representation of the arterial polygon was demonstrated, first, was Giulio Casserio who died leaving 86 anatomical drawings, followed by Adriaan van den Spiegel who again left an anatomical treatise to his successor Daniel Bucretius who illustrated it and presented the first well-described arterial polygon with a complete connection. In this era, another variant was described which was weak left PCOM as it seemed to be formed of two thin vessels [44, 48, 49].

Later, Johann Vesling described the arterial polygon in a nearly perfect way yet did not recognize the posterior cerebral artery (PCA) and was still considering the smaller branches and perforators as rete mirabile [50, 51].

Six years earlier to Willis's description, Johann Jakob Wepfer von Schaffhausen described in detail the arterial polygon with an emphasis on the splitting and anastomosis of the ICA, ACA, VA. Von Schaffhausen also focused on the perforators and their anastomosis. If the arterial polygon is not to be named after von Schaffhausen as some scholars suggest then his credit would be the proper identification of branching and anastomosing arteries forming the brain arterial tree rather than the ordinary vasculature joining artery to vein as in the rest of the body [44].

Thomas Willis working together with Richard Lower, and Thomas Millington was able to describe in full detail with illustrations the arterial polygon at the base of the skull, and with the ability to inject dye into the carotids the anastomosis and the collateral circulation was also identifiable. Willis as von Schaffhausen highlighted the value of the arterial anastomotic tree in its ability to overcome obstructed vessels by redirecting blood flow through other pathways protecting the brain in case of an occluded artery. It was not before 100 years later that Sir Thomas Willis's name was placed on the arterial polygon and named the circle of Willis [44].

Management of stroke from antiquities onwards

Being a disorder that has been known, since the dawn of civilizations attempts were made to overcome its burden. Attempts at management in antiquities were not much preserved either on the temples, papyri, or tablets. Yet as it was conceived as a strike from superpowers it was mostly managed by priests and was considered a punishment [30, 36].

Diseases including stroke in the Greco-Roman era were conceived as an imbalance between the four fluids which was the basis of the humoral theory of Hippocrates. Meanwhile, Galen conceived stroke as an obstruction to the spirit that passes from the heart into the rete mirabile at the skull base. Such obstruction was not considered secondary to blood clot development rather it was due to the organization of one of the body fluids. Muslims in the golden age assumed that thick blood caused occlusion of vessels and might be the reason behind the stroke [6].

Although rejected by Paracelsus in the sixteenth century, the humoral theory was still the approved explanation up to the nineteenth century and only competed by the punishment or curse theories [52].

Being secondary to an excess of one of the four fluids or failure to get it out of the body through different passages including defecation, stroke was managed by bizarre ways including enemas and suppositories to restore the balance between the fluids of the body. The only rational idea in management at that time was to get rid of the waste blood through cupping and later by venesection [6].

Natural remedies and ingredients were applied orally, nasally, or topically in different stages of stroke, such natural remedies were described and used as a common practice by Ibnisina in Canon of Medicine. Despite these ingredients not anymore used in modern medicine yet they were used based on their role in healing, neuroprotection, antioxidant, blood pressure lowering, and fibrinolytic role as being identified in modern medicine [53].

Ingredients that were used and modern medicine classifies as antioxidants are (Pistacia lentiscus L., Piper longum L., Rosa damascena Mill, Zingiber officinale Roscoe) as for neuroprotective agents (Citrus medica L., Matricaria chamomilla Blanco, Piper nigrum L.), blood pressure lowering (Zingiber officinale Roscoe, Ferula persica Willd.) and fibrinolytic (Elettaria cardamomum (L.) Maton). The Canon of Medicine of the tenth century continued to be a source of diagnosis and management of different disorders including stroke in Europe up to the seventeenth century [53].

Secondary prevention was achieved with the discovery of antiplatelets and statins and with the identification of atherosclerosis [13, 54, 55]. Acetylsalicylic acid (Aspirin) was first introduced in 1899 as a potent treatment for pain and fever and in 1900 was patented. It took 60 years for scientists to prove in the 1960s that aspirin acts on platelet aggregation and prevents thrombosis in laboratory experimental animals. In 1978 aspirin showed a role in reducing the risk of stroke and soon was approved in clinical trials to be effective against stroke [56, 57]. Meanwhile, 2 years earlier in 1976 statins were discovered yet it was not until 1984 that the first statin was approved [54].

In the 1960s, dipyridamole was introduced as a coronary vasodilator. Soon, it was approved as an antithrombotic that can inhibit platelet adhesiveness [58].

In 1972 and onwards through the 1980s, the irreversible platelet ADP antagonist ticlopidine was developed and was proved to be effective in stroke by 1989 [59].

In 1988, cilostazol which is a phosphodiesterase III inhibitor was manufactured in Japan as a derivative of cilostamide that prevents platelet reactivity and aggregation and acts as a vasodilator. In 2015, cilostazol was approved in Japan for secondary prevention of stroke, and in 2021, it was further approved in Asia as an add-on to other antiplatelets in non-cardioembolic strokes or transient ischemic attacks with intracranial or extracranial arterial stenosis or multiple vascular risk factors yet, it is not approved in Europe and only has a level of evidence C in USA [60].

By the 1990s, clopidogrel as a derivative of ticlopidine was developed and showed efficacy in clinical protection against ischemic insults [